Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII.

In this work, different series of benzothiazole-based sulphonamides 8a-c, 10, 12, 16a-b and carboxylic acids 14a-c were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b . In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12 . In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b , and the carboxylic acid derivatives 14a-c , respectively. All compounds ( 8a-c, 10, 12, 14a-c and 16a-b ) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.